Related Experiment Video

Updated: Oct 1, 2025

High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
05:33

High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines

Published on: November 9, 2020

10.2K

Selective Wee1 degradation by PROTAC degraders recruiting VHL and CRBN E3 ubiquitin ligases

Marine C Aublette1, Tom A Harrison1, Elizabeth J Thorpe1

  • 1Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YG, United Kingdom.

Bioorganic & Medicinal Chemistry Letters
|March 1, 2022
PubMed

Insights

Researchers developed novel PROTACs to selectively degrade Wee1 kinase, a target for cancer therapy. These PROTACs, derived from the Wee1 inhibitor AZD1775, show promise in overcoming off-target effects and enhancing cancer cell sensitivity.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Wee1 kinase regulates the G2/M cell cycle checkpoint by phosphorylating CDK1.
  • Inhibiting Wee1 can sensitize cancer cells to DNA-damaging agents.
  • The Wee1 inhibitor AZD1775 has shown off-target effects on other kinases.

Purpose of the Study:

  • To synthesize and evaluate Proteolysis-Targeting Chimeras (PROTACs) for selective Wee1 degradation.
  • To overcome the off-target effects of AZD1775 by inducing targeted protein degradation.
  • To explore the impact of different linkers and E3 ligase ligands on PROTAC efficacy.

Main Methods:

  • Synthesis of PROTACs by conjugating AZD1775 to VHL or CRBN ligands via various linkers.
  • Assessment of Wee1 degradation mediated by the synthesized PROTACs.
  • Evaluation of linker properties and E3 ligase recruitment for selective degradation.

Main Results:

  • PROTACs derived from AZD1775 successfully induced selective Wee1 degradation.
  • Degradation efficiency was dependent on the specific linker and E3 ligase ligand used.
  • PROTACs demonstrated improved selectivity compared to the parent inhibitor AZD1775.

Conclusions:

  • PROTAC technology can be effectively applied to achieve selective degradation of Wee1 kinase.
  • Targeted protein degradation offers a promising strategy to enhance the efficacy of cancer therapies.
  • Further optimization of PROTACs could lead to more effective and selective cancer treatments.
Keywords:
CDK1CereblonCheckpoint inhibitionPROTACTargeted degradationVHLWee1

More Related Videos

In Vitro Analysis of E3 Ubiquitin Ligase Function06:06

In Vitro Analysis of E3 Ubiquitin Ligase Function

Published on: May 14, 2021

5.5K
Cycloheximide Chase Analysis of Protein Degradation in Saccharomyces cerevisiae09:05

Cycloheximide Chase Analysis of Protein Degradation in Saccharomyces cerevisiae

Published on: April 18, 2016

29.3K

Related Concept Videos

Regulated Protein Degradation02:58

Regulated Protein Degradation

It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
7.8K
The Proteasome02:18

The Proteasome

Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
9.2K
Covalently Linked Protein Regulators02:04

Covalently Linked Protein Regulators

Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
7.6K
Export of Misfolded Proteins out of the ER01:32

Export of Misfolded Proteins out of the ER

After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
4.0K
The Unfolded Protein Response01:37

The Unfolded Protein Response

The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
5.2K
Anaphase Promoting Complex00:50

Anaphase Promoting Complex

The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
3.0K